BACKGROUND Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

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Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. methods Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. results The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progressionfree survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. conclusions The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.

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Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or

https://science.sciencemag.org/content/sci/early/2004/04/29/science.1099314.full.pdf

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?

Photodynamic therapy for cancer

BACKGROUND In a phase 1–2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel–gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel–gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel–gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel–gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel–gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.)

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Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine

Assessing the combination of FOLFOX or FOLFIRI with bevacizumab, cetuximab, or both in metastatic colorectal cancer

Patients often come to oncology clinics surrounded by family, friends, clergy, and others to provide emotional support, translate medical rhetoric, and take notes from the visits. Our patients themselves are mothers and fathers, sisters and brothers, friends, and, in some particularly trying scenarios, sons and daughters. They are real people who are facing the biggest challenge of their lives: their survival. Our patients remind us every day of the frailty of all our lives. All too often, we dehumanize our patients when providing care and also in our professional communications. We label our patients with cancer as “cancer patients.” We do this during rounds, in presentations, in publications, and in the press. This connotation seems to emphasize the disease over the patients themselves. Oncologists and members of the cancer care delivery team are faced with numerous unprecedented challenges, including caring for an increasing number of patients; learning the usage and side effects of increasing numbers of new drugs; taking the time to understand the biology underlying new pathways, drugs, and biomarkers; and learning new approaches and technologies with which to select and refine therapy. The increasing complexity of providing the best care for patients can lead to physician/care provider burnout. Provider stress and burnout does not just affect the provider, but negatively impacts our patients as well. When the health care team is overwhelmed, it may be too easy to forget that it is a privilege to care for patients, and that we must maintain our empathy and sympathy for our patients and their families at all times. This balancing act can be challenging, and so it is imperative to hit the “reset” button from time to time and remember that our patients are human beings deserving of our respect, concern, and empathy throughout the entire course of their care, including the palliative phase (if and when this occurs). What does it mean to be a person with cancer? The old adage about understanding others and developing empathy, “. . .walk a mile in their shoes,” is fitting. How many cancer care providers are themselves patients with a lifethreatening or life-altering disease? It feels very different to be a patient with cancer or a serious illness one day and a cancer care provider the next. As providers, we know that building a trusting relationship with our patients is paramount to providing the best care, both physically and psychologically. Taking the time to do so shows that we recognize our patients’ fears, challenges, emotions, and anxiety, and that we see and respect them as people first and patients second. “Cancer patient” is a catchall term, a dehumanizing label, a category within a population described in percentages. Percentages are fractions of the whole. Indirectly, the term “cancer patient” can suggest the person is less than whole. Alternatively, using the term “patient with cancer” reinforces the individuality of each person who happens to have cancer. Each patient has his or her own story, challenges, treatment susceptibilities, and, of course, their own genetic fingerprint. To recognize this is to return to the patient their personhood. The best way to reinforce this, including teaching the next generation of care providers, is to make a concerted effort to always use the term “patients with XX cancer” in all our professional discourse. It is a small change in semantics that makes a big difference in respect for our patients. This principle extends beyond patients with cancer; it is an important humanizing effort for all providers toward all patients.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.30625

Words matter: Restoring respect and dignity when referring to individuals with cancer

4113 Background: The treatment of pts with advanced biliary cancers represents a therapeutic challenge. The vascular endothelial growth factor and epidermal growth factor receptor pathways play an ...

SWOG 0941: A phase II study of sorafenib and erlotinib in patients (pts) with advanced gallbladder cancer or cholangiocarcinoma.

This is a phase I dose-escalation study of uracil and tegafur (in a molar ratio of 4:1 [UFT]) administered in combination with calcium folinate and paclitaxel in metastatic breast cancer. This trial was initiated to 1)

Charles D. Blanke

Papers

Assessing the combination of FOLFOX or FOLFIRI with bevacizumab, cetuximab, or both in metastatic colorectal cancer

Words matter: Restoring respect and dignity when referring to individuals with cancer

SWOG 0941: A phase II study of sorafenib and erlotinib in patients (pts) with advanced gallbladder cancer or cholangiocarcinoma.

Paclitaxel, UFT, and calcium folinate in metastatic breast cancer.

KIT as a Therapeutic Target